Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis.

As effector innate immune cells and as a host to the protozoan parasite Leishmania, macrophages play a dual role in antileishmanial immunoregulation. The 2 key players in this immunoregulation are the macrophage-expressed microRNAs (miRNAs) and the macrophage-secreted cytokines. miRNAs, as small noncoding RNAs, play vital roles in macrophage functions including cytokines and chemokines production. In the reverse direction, Leishmania-regulated cytokines alter miRNAs expression to regulate the antileishmanial functions of macrophages. The miRNA patterns vary with the time and stage of infection. The cytokine-regulated macrophage miRNAs not only help parasite elimination or persistence but also regulate cytokine production from macrophages. Based on these observations, we propose a novel immunoregulatory framework as a scientific rationale for antileishmanial therapy.

Leishmania donovani mitogen-activated protein kinases as a host-parasite interaction interface.

Leishmaniasis, a major globally re-emerging neglected tropical disease, has a restricted repertoire of chemotherapeutic options due to a narrow therapeutic index, drug resistance, or patient non-compliance due to toxicity. The disease is caused by the parasite Leishmania that resides in two different forms in two different environments: as sessile intracellular amastigotes within mammalian macrophages and as motile promastigotes in sandfly gut. As mitogen-activated protein kinases (MAPKs) play important roles in cellular differentiation and survival, we studied the expression of Leishmania donovani MAPKs (LdMAPKs). The homology studies by multiple sequence alignment show that excepting LdMAPK1 and LdMAPK2, all thirteen other LdMAPKs share homology with human ERK and p38 isoforms. Expression of LdMAPK4 and LdMAPK5 is less in avirulent promastigotes and amastigotes. Compared to miltefosine-sensitive L. donovani parasites, miltefosine-resistant parasites have higher LdMAPK1, LdMAPK3-5, LdMAPK7-11, LdMAPK13, and LdMAPK14 expression. IL-4-treatment of macrophages down-regulated LdMAPK11, in virulent amastigotes whereas up-regulated LdMAPK5, but down-regulated LdMAPK6, LdMAPK12-15, expression in avirulent amastigotes. IL-4 up-regulated LdMAPK1 expression in both virulent and avirulent amastigotes. IFN-γ-treatment down-regulated LdMAPK6, LdMAPK13, and LdMAPK15 in avirulent amastigotes but up-regulated in virulent amastigotes. This complex profile of LdMAPKs expression among virulent and avirulent parasites, drug-resistant parasites, and in amastigotes within IL-4 or IFN-γ-treated macrophages suggests that LdMAPKs are differentially controlled at the host-parasite interface regulating parasite survival and differentiation, and in the course of IL-4 or IFN-γ dominated immune response.

Interleukin-7 potentiates MAPK10-elicited host-protective vaccine against Leishmania donovani.

Leishmania donovani causes the potentially fatal disease visceral leishmaniasis for which neither a vaccine nor an adjuvant for human use exists. Although interleukin-7 (IL-7) is implicated in CD4+ T-cell response stabilization, its anti-leishmanial function is uncertain. Therefore, we examined whether IL-7 would potentiate the efficacy of Leishmania major-expressed MAPK10 (LmjMAPK10; M10)-elicited anti-leishmanial host-protective response. We observed that aligning with IL-7R expression, IL-7 increased IFN-γ-secreting TH1 cell but reduced IL-4-producing TH2 cells and production of IL-10 and TGF-ß effectuating anti-leishmanial functions in susceptible BALB/c mouse-derived macrophages. Co-culturing IL-7-pre-treated L. donovani-infected macrophages with L. donovani-infected BALB/c-derived T cells induced IFN-γ-dominated TH1 type anti-leishmanial function. IL-7 treatment of L. donovani-infected BALB/c mice significantly reduced splenic and hepatic parasite loads. Co-culturing CD4+ T cells from IL to 7-treated mice with L. donovani-infected macrophages reduced amastigote numbers suggesting IL-7-elicited host-protective effector T cells. Priming BALB/c with M10 + IL-7 reduced the splenic parasite burden more effectively than that was observed in M10-primed mice. An enhanced protection against L. donovani infection was accompanied by enhanced IL-12 and IFN-γ, but suppressed IL-10 and IL-4, response and host-protective TH1 and memory T cells. These results indicate IL-7-induced leishmanial antigen-specific memory T cell response that protects a susceptible host against L. donovani infection.

Understanding Antiferromagnetic and Ligand Field Effects on Spin Crossover in a Triple-Decker Dimeric Cr(II) Complex.

Two possible explanations for the temperature dependence of spin-crossover (SCO) behavior in the dimeric triple-decker Cr(II) complex ([(η5-C5Me5)Cr(µ2:η5-P5)Cr(η5-C5Me5)]+) have been offered. One invokes variations in antiferromagnetic interactions between the two Cr(II) ions, whereas the other posits the development of a strong ligand-field effect favoring the low-spin ground state. We perform multireference electronic structure calculations based on the multiconfiguration pair-density functional theory to resolve these effects. We find quintet, triplet, and singlet electronic ground states, respectively, for the experimental geometries at high, intermediate, and low temperatures. The ground-state transition from quintet to triplet at an intermediate temperature derives from increased antiferromagnetic interactions between the two Cr(II) ions. By contrast, the ground-state transition from triplet to singlet at low temperature can be attributed to increased ligand-field effects, which dominate with continued variations in antiferromagnetic coupling. This study provides quantitative detail for the degree to which these two effects can act in concert for the observed SCO behavior in this complex and others subject to temperature-dependent variations in geometry.

Broad Electronic Modulation of Two-Dimensional Metal-Organic Frameworks over Four Distinct Redox States.

Two-dimensional (2D) inorganic materials have emerged as exciting platforms for (opto)electronic, thermoelectric, magnetic, and energy storage applications. However, electronic redox tuning of these materials can be difficult. Instead, 2D metal-organic frameworks (MOFs) offer the possibility of electronic tuning through stoichiometric redox changes, with several examples featuring one to two redox events per formula unit. Here, we demonstrate that this principle can be extended over a far greater span with the isolation of four discrete redox states in the 2D MOFs LixFe3(THT)2 (x = 0-3, THT = triphenylenehexathiol). This redox modulation results in 10,000-fold greater conductivity, p- to n-type carrier switching, and modulation of antiferromagnetic coupling. Physical characterization suggests that changes in carrier density drive these trends with relatively constant charge transport activation energies and mobilities. This series illustrates that 2D MOFs are uniquely redox flexible, making them an ideal materials platform for tunable and switchable applications.

Elucidating Actinide-Pertechnetate and Actinide-Perrhenate Bonding via a Family of Th-TcO4 and Th-ReO4 Frameworks and Solutions.

Technetium-99, a ß-emitter produced from 235U fission, poses a challenge for the nuclear industry due to co-extraction of pertechnetate (TcO4-) with the actinides (An) during nuclear fuel reprocessing. Previous studies suggested that direct coordination of pertechnetate with An plays an important role in the coextraction process. However, few studies have provided direct evidence for An-TcO4- bonding in the solid state, and even fewer in solution. The present study describes synthesis and structural elucidation of a family of thorium(IV)-pertechnetate/perrhenate (ReO4-, nonradioactive surrogate) compounds, which is obtained by dissolution of thorium oxyhydroxide in perrhenic/pertechnic acid followed by crystallization, with or without heating. For reaction ratios of 3:1, 4:1, and 6:1 MO4-/Th(IV) (M = Tc, Re), the crystallized compounds reflect the same ratio, suggesting facile and flexible coordination. Nine structures reveal 1-dimensional and 2-dimensional frameworks with varying topologies. While a multitude of compounds isolated from 4:1 (and 6:1) reaction solutions feature Th monomers linked by MO4-, the 3:1 reaction solution yielded the well-known dihydroxide-bridged thorium dimer, linked, and capped by MO4-. Density functional theory calculations on ReO4-/TcO4- isomorphs suggest similar bonding characteristics in the solid state, but experimental solution characterization noted differences. Specifically, small-angle X-ray scattering studies suggest the bonding of Th-TcO4- persists in solution, while Th-ReO4- bonding is less apparent.

Theoretical Investigation of Single-Molecule-Magnet Behavior in Mononuclear Dysprosium and Californium Complexes.

Early-actinide-based (U, Np, and Pu) single-molecule magnets (SMMs) have yet to show magnetic properties similar to those of highly anisotropic lanthanide-based ones. However, there are not many studies exploring the late-actinides (more than half-filled f shells) as potential candidates for SMM applications. We computationally explored the electronic structure and magnetic properties of a hypothetical Cf(III) complex isostructural to the experimentally synthesized Dy(dbm)3(bpy) complex (bpy = 2,2'-bipyridine; dbm = dibenzoylmethanoate) via multireference methods and compared them to those of the Dy(III) analogue. This study shows that the Cf(III) complex can behave as a SMM and has a greater magnetic susceptibility compared to other experimentally and computationally studied early-actinide-based (U, Np, and Pu) magnetic complexes. However, Cf spontaneously undergoes α-decay and converts to Cm. Thus, we also explored the isostructural Cm(III)-based complex. The computed magnetic susceptibility and g-tensor values show that the Cm(III) complex has poor SMM behavior in comparison to both the Dy(III) and Cf(III) complexes, suggesting that the performance of Cf(III)-based magnets may be affected by α-decay and can explain the poor performance of experimentally studied Cf(III)-based molecular magnets in the literature. Further, this study suggests that the ligand field is dominant in Cf(III), which helps to increase the magnetization blocking barrier by nearly 3 times that of its 4f congener.

Multiconfiguration Pair-Density Functional Theory for Vertical Excitation Energies in Actinide Molecules.

Modeling actinides with electronic structure theories is challenging because these systems present a strong ligand field and metal-ligand covalency. We systematically investigate the effectiveness of pair-density functional theory (PDFT) for the calculation of vertical excitation energies in An(III), [AnIIICl6]3-, and [AnVIO2]2+ (An = U, Np, Pu, and Am). We compare the performance of PDFT, hybrid PDFT, and multistate PDFT with traditional active-space methods followed by perturbation theory, like multistate CASPT2, and with experimental data. Overall, multistate PDFT gives quantitative agreement with multistate CASPT2 at a significantly reduced computational cost.

Siah2-GRP78 interaction regulates ROS and provides a proliferative advantage to Helicobacter pylori-infected gastric epithelial cancer cells.

Helicobacter pylori-mediated gastric carcinogenesis involves upregulation of the E3 ubiquitin ligase Siah2 and its phosphorylation-mediated stabilization. This study elucidates a novel mechanism of oxidative stress regulation by phosphorylated Siah2 in H. pylori-infected gastric epithelial cancer cells (GECs). We identify that H. pylori-mediated Siah2 phosphorylation at the 6th serine residue (P-S6-Siah2) enhances proteasomal degradation of the 78-kDa glucose-regulated protein (GRP78) possessing antioxidant functions. S6 phosphorylation stabilizes Siah2 and P-S6-Siah2 potentiates H. pylori-mediated reactive oxygen species (ROS) generation. However, infected S6A phospho-null Siah2-expressing cells have decreased cellular GRP78 level as surprisingly these cells release GRP78 to a higher extent and accumulate significantly higher ROS than the wild type (WT) Siah2 construct-expressing cells. Ectopic expression of GRP78 prevents the loss of mitochondrial membrane potential and cellular ROS accumulation caused by H. pylori. H. pylori-induced mitochondrial damage and mitochondrial membrane potential loss are potentiated in Siah2-overexpressing cells but these effects are further enhanced in S6A-expressing cells. This study also confirms that while phosphorylation-mediated Siah2 stabilization optimally upregulates aggresome accumulation, it suppresses autophagosome formation, thus decreasing the dependency on the latter mechanism in regulating cellular protein abundance. Disruption of the phospho-Siah2-mediated aggresome formation impairs proliferation of infected GECs. Thus, Siah2 phosphorylation has diagnostic and therapeutic significance in H. pylori-mediated gastric cancer (GC).

Anti-leishmanial therapy: Caught between drugs and immune targets.

Leishmaniasis is an enigmatic disease that has very restricted options for chemotherapy and none for prophylaxis. As a result, deriving therapeutic principles for curing the disease has been a major objective in Leishmania research for a long time. Leishmania is a protozoan parasite that lives within macrophages by subverting or switching cell signaling to the pathways that ensure its intracellular survival. Therefore, three groups of molecules aimed at blocking or eliminating the parasite, at least, in principle, include blockers of macrophage receptor- Leishmania ligand interaction, macrophage-activating small molecules, peptides and cytokines, and signaling inhibitors or activators. Macrophages also act as an antigen-presenting cell, presenting antigen to the antigen-specific T cells to induce activation and differentiation of the effector T cell subsets that either execute or suppress anti-leishmanial functions. Three groups of therapeutic principles targeting this sphere of Leishmania-macrophage interaction include antibodies that block pro-leishmanial response of T cells, ligands that activate anti-leishmanial T cells and the antigens for therapeutic vaccines. Besides these, prophylactic vaccines have been in clinical trials but none has succeeded so far. Herein, we have attempted to encompass all these principles and compose a comprehensive review to analyze the feasibility and adoptability of different therapeutics for leishmaniasis.

The expression of PD-1 and its ligands increases in Leishmania infection and its blockade reduces the parasite burden.

The expression of programmed cell death protein-1 (PD-1) and its ligands- PD-L1 and PD-L2- on T cells and macrophages', respectively, increases in Leishmania infection. The PD-1/PD-L1 interaction induces T cell anergy, T cell apoptosis and exhaustion, diversion of T cells toward TH2 and T-reg cells but inhibits M1 macrophage activities by suppression of nitric oxide (NO) and reactive oxygen species (ROS) production. These changes exacerbate Leishmania infection. As PD-L1-deficient, but not PD-L2-deficient, mice were protected againstL. mexicanainfection, differential roles have been proposed for PD-L1 and PD-L2 in mouse models of leishmaniasis. Blockade of PD-1/PD-L1 interaction in various in vitro and Leishmania-infected mouse, hamster and dog models enhanced IFN-γ and NO production, reduced IL-10 and TGF-ß generation, promoted T cell proliferation and reduced parasite burden. Therefore, PD-1/PD-L1 blockade is being considered as a potential therapeutic strategy to restore protective immunity during leishmaniasis, particularly, in drug-resistant cases.

Development and Characterization of an Avirulent Leishmania major Strain.

Leishmania major causes cutaneous leishmaniasis. An antileishmanial vaccine for humans is unavailable. In this study, we report development of two attenuated L. major strains-5ASKH-HP and LV39-HP-by continuous culture (high passage) of the corresponding virulent strains (low passage). Both avirulent strains showed similar changes in proteome profiles when analyzed by surface-enhanced laser desorption ionization mass spectrometry. Liquid chromatography-mass spectrometry and microarray characterization of 5ASKH strains revealed substantially altered gene and protein expression profiles, respectively. Both virulent and avirulent L. major strains grew comparably in culture, but the avirulent strain survived significantly less in BALB/c-derived peritoneal macrophages. Both attenuated strains failed to infect BALB/c mice and elicited IFN-γ, but not IL-4 and IL-10, responses. 5ASKH-HP parasites failed to induce significant infection even in severely immunocompromised- SCID or inducible NO synthase-, CD40-, or IL-12-deficient mice, indicating attenuation. The avirulent strain induced less IL-10, but higher IL-12, in macrophages. The avirulent strain failed to reduce CD40 relocation to the detergent-resistant membrane domain and to inhibit CD40-induced phosphorylation of the kinases Lyn and protein kinase C-ß and MAPKs MKK-3/6 and p38MAPK or to upregulate MEK-1/2 and ERK-1/2 in BALB/c-derived peritoneal macrophages. The virulent and the avirulent strains reciprocally modulated CD40-induced Ras-mediated signaling through PI-3K and Raf-1. Avirulent 5ASKH-primed BALB/c mice were protected against virulent L. major challenge infection. The loss of virulence accompanied by substantially altered proteome profiles and the elicitation of host-protective immune responses indicate plausibly irreversible attenuation of the L. major strain and its potential use as a vaccine strain.

Linker Redox Mediated Control of Morphology and Properties in Semiconducting Iron-Semiquinoid Coordination Polymers.

The emergence of conductive 2D and less commonly 3D coordination polymers (CPs) and metal-organic frameworks (MOFs) promises novel applications in many fields. However, the synthetic parameters for these electronically complex materials are not thoroughly understood. Here we report a new 3D semiconducting CP Fe5 (C6 O6 )3 , which is a fusion of 2D Fe-semiquinoid materials and 3D cubic Fex (C6 O6 )y materials, by using a different initial redox-state of the C6 O6 linker. The material displays high electrical conductivity (0.02 S cm-1 ), broad electronic transitions, promising thermoelectric behavior (S2 σ=7.0×10-9  W m-1 K-2 ), and strong antiferromagnetic interactions at room temperature. This material illustrates how controlling the oxidation states of redox-active components in conducting CPs/MOFs can be a "pre-synthetic" strategy to carefully tune material topologies and properties in contrast to more commonly encountered post-synthetic modifications.

TLR2 dimer-specific ligands selectively activate protein kinase C isoforms in Leishmania infection.

Of the thirteen Toll-like receptors (TLRs) in mice, TLR2 has a unique ability of forming heterodimers with TLR1 and TLR6. Such associations lead to selective cellular signalling and cellular responses such as cytokine expression. One of the signalling intermediates is protein kinase C (PKC); of which, eight isoforms are expressed in macrophages. Leishmania-a protozoan parasite that resides and replicates in macrophages-selectively modulates PKC-α, PKC-ß, PKC-δ and PKC-ζ isoforms in macrophages. As TLR2 plays significant roles in Leishmania infection, we examined whether these PKC isoforms play selective roles in TLR2 signalling and TLR2-induced anti-leishmanial functions. We observed that the TLR2 ligands-Pam3 CSK4 (TLR1/2), PGN (TLR2/2) and FSL (TLR2/6)-differentially phosphorylated and translocated PKC-α, PKC-ß, PKC-δ and PKC-ζ isoforms to cell membrane in uninfected and L. major-infected macrophages. The PKC isoform-specific inhibitors differentially altered IL-10 and IL-12 expression, Th1 and Th2 responses and anti-leishmanial effects in macrophages and in BALB/c mice. While PKC isoforms' inhibitors had insignificant effects on the Pam3CSK4-induced anti-leishmanial functions, PGN-induced pro-leishmanial effects were enhanced by PKC-(α + ß) inhibitors, whereas PKC-(δ + Î¶) inhibitors enhanced the anti-leishmanial effects of FSL. These results indicated that the ligand-induced TLR2 dimerization triggered differential dose-dependent and kinetic profiles of PKC isoform activation and that selective targeting of PKC isoforms using their respective inhibitors in combination significantly modulated TLR2-induced anti-leishmanial functions. To the best of our knowledge, this is the first demonstration of TLR2 dimer signalling through PKC isoforms and TLR2-induced PKC isoform-targeted anti-leishmanial therapy.

Interdependencies between Toll-like receptors in Leishmania infection.

Multiple pathogen-associated molecular patterns (PAMPs) on a pathogen's surface imply their simultaneous recognition by the host cell membrane-located multiple PAMP-specific Toll-like receptors (TLRs). The TLRs on endosomes recognize internalized pathogen-derived nucleic acids and trigger anti-pathogen immune responses aimed at eliminating the intracellular pathogen. Whether the TLRs influence each other's expression and effector responses-termed TLR interdependency-remains unknown. Herein, we first probed the existence of TLR interdependencies and next determined how targeting TLR interdependencies might determine the outcome of Leishmania infection. We observed that TLRs selectively altered expression of their own and of other TLRs revealing novel TLR interdependencies. Leishmania major-an intra-macrophage parasite inflicting the disease cutaneous leishmaniasis in 88 countries-altered this TLR interdependency unfolding a unique immune evasion mechanism. We targeted this TLR interdependency by selective silencing of rationally chosen TLRs and by stimulation with selective TLR ligands working out a novel phase-specific treatment regimen. Targeting the TLR interdependency elicited a host-protective anti-leishmanial immune response and reduced parasite burden. To test whether this observation could be used as a scientific rationale for treating a potentially fatal L. donovani infection, which causes visceral leishmaniasis, we targeted the inter-TLR dependency adopting the same treatment regimen. We observed reduced splenic Leishman-Donovan units accompanied by host-protective immune response in susceptible BALB/c mice. The TLR interdependency optimizes TLR-induced immune response by a novel immunoregulatory framework and scientifically rationalizes targeting TLRs in tandem and in sequence for redirecting immune responses against an intracellular pathogen.

Role of thrombopoiesis in leishmaniasis.

The blood vascular system of mammals is unique in nature; inhabited with a pool of tiny small cell fragments called platelets; attributed with the most important patrolling tasks to check integrity of the entire endothelial landscape. Their production is tightly coupled with hematopoietic system where everything starts from self renewable multipotent hematopoietic stem cells (HSCs) which eventually undergo dual step (megakaryopoiesis-thrombopoiesis) thrombocytes production. Several cytokines tune the fate of every progenitor cells during hematopoiesis through temporal activation of specific transcription factors. Though platelets generated through steady state hematopoiesis are involved in the regulation of vascular homeostasis, these cells can sense pathogens through its innate immune sensors and can mount crucial responses against the invading pathogen. For this, the primary aim of many infections including Leishmania is to induce thrombocytopenia within infected host. But the underlying mechanism of this induced thrombocytopenia in Leishmania infection has not been evaluated. Elucidation of these mechanisms will be fruitful to design new chemotherapeutic strategies.

A primer on cytokines.

Cytokines are pleiotropic polypeptides that control the development of and responses mediated by immune cells. Cytokine classification predominantly relies on [1] the target receptor(s), [2] the primary structural features of the extracellular domains of their receptors, and [3] their receptor composition. Functionally, cytokines are either pro-inflammatory or anti-inflammatory, hematopoietic colony-stimulating factors, developmental and would healing maintaining immune homeostasis. When the balance in C can form complex networks amongst themselves that may affect the homeostasis and diseases. Cytokines can affect resistance and susceptibility for many diseases and their availability in the host cytokine production and interaction is disturbed, immunopathogenesis sets in. Therefore, cytokine-targeting bispecific, and chimeric antibodies form a significant mode of immnuo-therapeutics Although the field has grown deep and wide, many areas of cytokine biology remain unknown. Here, we have reviewed these cytokines along with the organization, signaling, and functions through respective cytokine-receptor-families. Being part of the special issue on the Role of Cytokines in Leishmaniasis, this review is intended to be used as an organized primer on cytokines and not a resource for detailed discussion- for which a two-volume Handbook of cytokines is available- on each of the cytokines. Priming the readers on cytokines, we next brief the role of cytokines in Leishmaniasis. In the brief, we do not provide an account of each of the involved cytokines known to date, instead, we offer a temporal relationship between the cytokines and the progress of the infection towards the alternate outcomes- healing or non-healing- of the infection.

Conundrums in leishmaniasis.

Parasites of the genus Leishmania cause the disease leishmaniasis. As the sandfly vector transfers the promastigotes into the skin of the human host, the infection is either cured or exacerbated. In the process, there emerge several unsolved paradoxes of leishmaniasis. Chronologically, as the infections starts in skin, the role of the salivary proteins in supporting the infection or the host response to these proteins influencing the induction of immunological memory becomes a conundrum. As the parasite invokes inflammation, the infiltrating neutrophils may act as "Trojan Horse" to transfer parasites to macrophages that, along with dendritic cells, carry the parasite to lymphoid organs to start visceralization. As the visceralized infection becomes chronic, the acutely enhanced monocytopoiesis takes a downturn while neutropenia and thrombocytopenia ensue with concomitant rise in splenic colony-forming-units. These responses are accompanied by splenic and hepatic granulomas, polyclonal activation of B cells and deviation of T cell responses. The granuloma formation is both a containment process and a form of immunopathogenesis. The heterogeneity in neutrophils and macrophages contribute to both cure and progression of the disease. The differentiation of T-helper subsets presents another paradox of visceral leishmaniasis, as the counteractive T cell subsets influence the curing or non-curing outcome. Once the parasites are killed by chemotherapy, in some patients the cured visceral disease recurs as a cutaneous manifestation post-kala azar dermal leishmaniasis (PKDL). As no experimental model exists, the natural history of PKDL remains almost a black box at the end of the visceral disease.

Cytokines and metabolic regulation: A framework of bidirectional influences affecting Leishmania infection.

Leishmania, a protozoan parasite inflicting the complex of diseases called Leishmaniases, resides and replicates as amastigotes within mammalian macrophages. As macrophages are metabolically highly active and can generate free radicals that can destroy this parasite, Leishmania also devise strategies to modulate the host cell metabolism. However, the metabolic changes can also be influenced by the anti-leishmanial immune response mediated by cytokines. This bidirectional, dynamic and complex metabolic coupling established between Leishmania and its host is the result of a long co-evolutionary process. Due to the continuous alterations imposed by the host microenvironment, such metabolic coupling continues to be dynamically regulated. The constant pursuit and competition for nutrients in the host-Leishmania duet alter the host metabolic pathways with major consequences for its nutritional reserves, eventually affecting the phenotype and functionality of the host cell. Altered phenotype and functions of macrophages are particularly relevant to immune cells, as perturbed metabolic fluxes can crucially affect the activation, differentiation, and functions of host immune cells. All these changes can deterministically direct the outcome of an infection. Cytokines and metabolic fluxes can bidirectionally influence each other through molecular sensors and regulators to dictate the final infection outcome. Our studies along with those from others have now identified the metabolic nodes that can be targeted for therapy.

Record High Magnetic Anisotropy in Three-Coordinate MnIII and CrII Complexes: A Theoretical Perspective.

Ab initio calculations performed in two three-coordinate complexes [Mn{N(SiMe3)2}3] (1) and [K(18-crown-6) (Et2O)2][Cr{N(SiMe3)2}3] (2) reveal record-high magnetic anisotropy with the D values -64 and -15 cm-1, respectively, enlisting d4 ions back in the race for single-ion magnets. A detailed spin-vibrational analysis performed of 1 and 2 suggests dominance under barrier relaxation due to the flexible coordination spheres around the metal ion. Furthermore, several in silico models were constructed by varying the nature of donor atoms based on the X-ray structure of 1 and 2, unveiling much larger anisotropy and robust single-ion magnet (SIM) characteristics for some of the models offering design clues for low-coordinate transition-metal SIMs.